Effects of fenoldopam, a specific dopamine receptor agonist, on blood pressure and left ventricular function in systemic hypertension.

Abstract

1 The effects of fenoldopam, an orally active, specific dopamine-1 receptor agonist, were studied in eleven patients with essential hypertension, using intra-arterial blood pressure recording and equilibrium gated radionuclide angiography. 2 A single dose of fenoldopam 100 mg produced a fall in blood pressure (BP) starting after 20 min. The maximum BP reduction (23/25 mm Hg) occurred after 50 min and was accompanied by a heart rate (HR) increase of 10 beats min-'. The acute effects on BP lasted for 130 min. 3 After 8 weeks of fenoldopam 100 mg, twice daily, only a small, statistically insignificant, hypotensive effect was still apparent after each dose of drug. The duration of the effect was too short to be clinically useful. Tilt-testing produced a BP fall of 24/14 mm Hg and a HR increase of 17 beats min1. Three patients experienced symptoms of postural hypotension during the study. 4 The drug attenuated the blood pressure rise produced by dynamic cycle exercise and isometric hand grip. 5 Acute administration of fenoldopam increased the left ventricular ejection fraction from 61% to 71% (P < 0.005) and increased the peak filling rate from 2.52 to 3.86 end diastolic vol s-1 (P < 0.002). After chronic fenoldopam administration, the left ventricular ejection fraction was 65% (P = NS) pre-dose, rising to 69% (P < 0.02) post-dose and the peak filling rate was increased from 2.7 to 3.38 end diastolic vol s-' (P < 0.01) 60 min postdose. There was also a significant increase of the first one-third filling fraction from 0.24 to 0.47 (P < 0.01) pre-dose, indicating improved diastolic function. 6 Although the duration of action of this formulation of fenoldopam is too short to recommend it for clinical use, a slow-release preparation would merit further investigation for treatment of hypertension and heart failure.

Medicinal Chemistry of CatecholO-Methyltransferase (COMT) Inhibitors and Their Therapeutic Utility

“…The COMT physiological substrates include dopamine, epinephrine, norepinephrine, 3,4-dihydroxymandelic acid (DOMA), 3,4-dihydroxyphenylacetic acid (DOPAC), ascorbic acid, and catechol estrogens, such as 2-hydroxyestradiol, 4-hydroxyestradiol, 2-hydroxyestrogen, 2-hydroxyestron, and the dihydroxyindolic intermediates of melanin. Several drugs incorporating a dihydroxyphenyl moiety are also substrates of COMT, including amino acid decarboxylase (AADC) inhibitors (carbidopa, 1 , and benserazide, 2 ), dopamine agonists (apomorphine, 3 , dobutamine, 4 , and fenoldopam, 5 ), the antihypertensive compound α-methyl-L-DOPA, 6 , and bronchodilating agents, such as isoprenaline, 7 , and rimiterol, 8 (Figure ). Moreover, COMT also plays a key role in the inactivation of exogenous toxic compounds and metabolites bearing catecholic structures.…”

“…These characteristic properties are thought to be of relevance in terms of the downstream clinical efficacy and safety of PD treatment and will be discussed in this perspective article along with the potential therapeutic applications of COMT inhibitors in other dopamine-deficiency related diseases. drugs incorporating a dihydroxyphenyl moiety are also substrates of COMT, including amino acid decarboxylase (AADC) inhibitors (carbidopa 1 18 and benserazide 2 19 ), dopamine agonists (apomorphine 3 20 , dobutamine 4 21 and fenoldopam 5 22 ), the antihypertensive compound alphamethyl-L-DOPA 6 23 and bronchodilating agents, such as isoprenaline 7 24 and rimiterol 8 25 ( Figure 2). Moreover, COMT also plays a key role in the inactivation of exogenous toxic compounds and metabolites bearing catecholic structures.…”

Targeting Metalloenzymes for Therapeutic Intervention

“…Unsurprisingly, inhibitors bearing a catechol MBP constitute the largest, most clinically advanced class of COMT inhibitors. ,,− In the 1960s, the first generation of COMT inhibitors appeared that contained a catechol MBP. − U-0521 (Figure ) is the most archetypal and potent inhibitor of this class ( K i = 7.8 μM); however, U-0521 displayed low selectivity (also inhibiting tyrosine hydroxylase), poor activity, and high toxicity. In addition, first generation inhibitors were often substrates for COMT themselves and underwent O -methylation.…”

Effects of intravenous fenoldopam (SK&F 82526-J) on blood pressure in severe hypertension

“…In a small group of patients [7], renal function was carefully monitored with hourly diuresis, and sodium and uric acid excretion. During the infusion diuresis was 89 +-15 ml/hr; in the 24 hours following the end of the infusion, diuresis remained constant at a rate of 50 -8 ml/hr.…”